TOXICOLOGY AND APPLIED PHARMACOLOGY lm,9-23 (1989) Structural Requirements for Anthracycline-Induced Cardiotoxicity and Antitumor Effects YOGENDRA SINGH, LINDAULRICH,DONNAKATZ, PATRICKBOWEN,AND GOPALKRISHNA’ Section on Drug Tissue Interaction, Laborat0r.v @Chemical Pharmacology, National Heart. Lung. and Blood Institute. National Institutes ofHealth. Bethesda, Maryland 20892 Received August 29, 1988; accepted April 22. 1989 Structural Requirements for Anthracycline-Induced Cardiotoxicity and Antitumor Effects. SINGH, Y., ULRICH, L.. KATZ, D.. BOWEN, P., AND KRISHNA, G. (1989). Toxicol. Appl. Phar- macol. 100,9-23. By employing rat cardiac myocytes in culture and mouse L-1210 leukemia cells, we have compared different anthracycline analogs with respect to their ability to kill cardiac myocytes and tumor cells. Anthracyclines induced a decrease in cellular ATP and glutathione from both cardiac myocytes and L- 12 10 cells in a time- and concentration-dependent fashion. Moreover, the decrease in ATP in cardiac myocytes was followed by release of the cytoplasmic enzyme lactic acid dehydrogenase and of adenine nucleotides after anthracycline treatment. At very low concentrations of anthracyclines, at which ATP and glutathione were not affected, the drugs induced complete cessation of the growth of L- I2 10 cells. Some structural alterations in the anthracycline molecule resulted in parallel changes in antitumor activity and in cardiotoxic- ity. But other structural alterations resulted in dissimilar changes in antitumor activity and car- diotoxicity. Although the results indicate that the structural requirements for inducing cardio- toxicity and antitumor activity may be different, they also indicate that the mechanisms by which anthracycline causes cell death in tumor cells and cardiac myocytes may be the same. t 1989 Academic Press. Inc The anthracyclines adriamycin and dauno- mycin are potentially among the most valu- able antitumor agents currently available be- cause of their spectrum of activity (Blum, 1975). Although several drugs are employed in cancer chemotherapy. in general, only an- thracycline antibiotics are known to cause cardiotoxicity (Unverferth et al., 1982: Shir- hatti et al., 1986) and cardiac myopathy, which limits their use as antitumor agents (Myers, 1984; Pence et al., 1983). Several mechanisms of toxicity have been proposed, including the release of histamine and cate- cholamines from damaged heart (Bristow et al., 1978) free radical generation and lipid peroxidation (Myers et al., 1977; Bachur et ’ To whom reprint requests should be addressed. al., 1978). mitochondrial damage (Ferrer0 et al., 1976) excess calcium influx (Olson et al.. 1974), interference in the Na’-K’ ATPase pump (Gosalvez et al., 1979) effect on nucleic acid and protein synthesis (Buja et ul.. 1973; Lewis et al., 1983) depletion of cellular ATP and GSH (Shirhatti et ul., 1986). and in- hibition of uptake of adenine, amino acids. and glucose (Reese et al., 1987). By contrast. anthracyclines are thought to elicit their anti- tumor effects through direct binding to DNA (DiMarco et ~1.. 1975: Schwartz and Kanter. 1979). Several analogs have been developed to re- duce cardiotoxicity and increase or retain an- titumor activity. For example, a doxorubicin analog, 3’-deamino-3’-(3 cyano4-morpholi- nyl)doxorubicin recently has been found to 9 0041-008X/89 $3.00 Copyright 1~. 1989 by Academic Press. Inc All rqhts of’rrproduct~n in ~“y for”, rr\ev et,